This invention relates to a process for preparing monosodium phosphoenolpyruvate and more particularly to a process for preparing monosodium phosphoenolpyruvate monohydrate, and use of the same as a visceral function improver.
Phosphoenolpyruvic acid (hereinafter referred to as PEP) is a phosphoric acid compound with high energy and particularly important compound, from the standpoint of biochemistry and enzymological chemistry, which produces adenosine-triphosphate (ATP) by reacting with adenocine-diphosphate (ADP).
Namely, in an organs or tissues of humans or other mammals, various disorders are caused if adenosine triphosphate is insufficient. For example, if an oxygen deficit due to ischemia is maintained in organs or tissues, the formation of ATP may become insufficient, resulting in causing morbidities such as cardiac infarction or renal insufficiency, respectively, in a heart or in a kidney. In order to cure such a disease, it is necessary to immediately supply tissue cells with ATP or any precursores thereof from outside of cells. But any substances useful for this purpose have not been found at all.
Accordingly, it has been desired to investigate a substance which is a high energy compound having good cell membrane permeability and capable of being intracellularly converted to a high energy compound such as ATP, and that can be a therapeutic agent for curing diseases, particularly an ischemic disease, more particularly an ischemic kidney disease or an ischemic heart disease, caused by the insufficiency of ATP, thereby aiming at effective utilization thereof as an improver for visceral functions.
Further, the above acid is used recently, in organic synthesis reactions utilizing enzyme catalysts (for example, Journal of Amer. Chem. Soc., Vol. 107, p. 7008 and Vol. 107, p. 7019, 1985) and considered to be useful also as a blood preservative.
PEP and derivatives thereof have long been chemically synthesized, as exemplified by a method wherein a halopyruvic acid and a trialkyl phosphite are used. However, in these conventionally known synthesis, PEP is produced in the form of an ester, and there has not been found any satisfactory method for producing PEP on an industrial scale, in an unesterified form, as is present in the natural world.
As processes for preparing the unesterified PEP, the following processes have been proposed to date:
(1) A process wherein pyruvic acid protected by a trimethylsilyl group and a derivative of phosphoric acid are used (Japanese Provisional Patent Publication No. 113789/1981). PA1 (2) A process wherein dialkylphosphoenolpyruvic acid is hydrolyzed and then monopotassium salt thereof is obtained by use of potassium hydroxide (Japanese Provisional Patent Publication No. 500515/1984). PA1 (3 ) A process wherein monobenzylphosphoenolpyruvic acid is hydrogenolyzed (Chem. Ber., Vol. 92, p. 952, 1959). PA1 (4) A process wherein PEP cyclohexylamine salt is converted into PEP by use of an ion exchange resin, followed by addition of an alkali hydroxide to obtain an aqueous solution of an alkali metal salt of PEP (Biochem. Prep., Vol. 11, p. 101, 1966). PA1 to hydrolysis, and also to a use of the above monosodium phosphoenolpyruvate prepared according to the above process as a visceral function improver, particularly for an ischemic disease, more particularly for an ischemic kidney disease or an ischemic heart disease.
In the above-described process (1), however, it is necessary to protect pyruvic acid with a trimethylsilyl group, and for said protection, trimethylsilyl chloride, which is costly, must be used. Moreover, the procedures employed therefor is complicated and PEP is formed as a trisodium salt. On the other hand, in the above-described process (2), while it can be expected that sodium salt of PEP may be obtained if sodium hydroxide is used instead of potassium hydroxide. After examination of such method, it was found that the monosodium salt of PEP with good purity could not be obtained. Further, in the above-described process (3), not only yield of monosodium salt of PEP produced is low but also the double bond in enol is hydro-genated to produce a large amount of by-products resulting in a complicated purification process. Also, in the above-described process (4), while there may be obtained an aqueous solution of an alkali metal salt of PEP, a product formed according to such a preparation method is unknown in its composition.